Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia.

Mithun Vinod Shah,Alexandra Higgins

doi:10.3390/genes11070749

Abstract

A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios.

Highlights

Acute myeloid leukemia (AML) can arise de novo or as a complication of a prior malignancy.Secondary leukemia can be classified into one of two broad entities: acute myeloid leukemia (AML) arising from an antecedent myeloid malignancy—myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or MDS/MPN overlap syndrome, where progression to AML is considered a part of the natural history of the disease (secondary AML)—as well as therapy-related myeloid neoplasm (t-MN), which arises as a complication of prior cytotoxic therapy (Figure 1)
Secondary leukemia can be classified into one of two broad entities: AML arising from an antecedent myeloid malignancy—myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or MDS/MPN overlap syndrome, where progression to AML is considered a part of the natural history of the disease (secondary AML)—as well as therapy-related myeloid neoplasm (t-MN), which arises as a complication of prior cytotoxic therapy (Figure 1)
Cells with lower level tumor protein 53 (TP53) activity out-compete cells with higher level of TP53 activity, and allow for competitive advantage of cells with reduced p53 activity [108]. This cell competition is demonstrated to occur at the level of hematopoietic stem cells (HSCs) and provides a mechanism for which TP53-mutated cells have selective advantage during cytotoxic therapies. These findings suggest that TP53 mutations are enriched in t-MN compared to de novo AML, and that this mutation may predate chemotherapy exposure and confer selective growth advantage to the cells harboring the mutated clone

Summary

Introduction

Acute myeloid leukemia (AML) can arise de novo or as a complication of a prior malignancy. Secondary leukemia can be classified into one of two broad entities: AML arising from an antecedent myeloid malignancy—myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or MDS/MPN overlap syndrome, where progression to AML is considered a part of the natural history of the disease (secondary AML (sAML))—as well as therapy-related myeloid neoplasm (t-MN), which arises as a complication of prior cytotoxic therapy (Figure 1). When combined, these entities account for 25–35% of all AML cases [1,2]. Secondary AML Arising from Myelodysplastic Syndrome (MDS) and MPN in Blast Phase

Secondary

Mutations in Epigenetic Regulators

Mutations in the Transcriptional Regulator Genes

Mutations in the Signaling Pathways

Mutational Landscape of Therapy-Related Myeloid Neoplasms

Biology of Therapy-Related Myeloid Neoplasm

The Role of Clonal Hematopoiesis in the Development of Myeloid Malignancies

Findings

Conclusions